The superposition of the DPP-Ⅳ complex revealed that the butynyl group of Linagliptin can be freely switched with the cyanobenzyl group of Alogliptin.Thus, a pharmacophore hybridization of A logliptin was initiated and led to a novel DPP-Ⅳ inhibitor, 11a.Although it did not exhibit the desired activity (IC50=0.2 μM), compound 1 1a acts as a lead compound, which triggeied a resulting structural optimization and the formation of compound 1 1m.A novel series of potent DPP-Ⅳ inhibitors represented by compound 11m (IC50=0.4 nM) was ultimately obtained with a robust pharmacokinetic profile and superior in vitro and in vivo efficacy compared to Alogliptin.